Project Summary: The effect of myocardial inflammation on stem cell effectiveness as ?repair cell? therapy Cardiovascular disease including myocardial infarction (MI) is the leading cause of death in the western world. Following MI, myocardial inflammation plays a crucial role in the pathogenesis of MI injury and macrophages are among the key cells activated during the initial phases of the host response regulating the healing process. Macrophages undergo phenotypic changes from pro-inflammatory (M1) towards an anti- inflammatory and wound healing phenotype (M2) through mechanisms that are not yet fully elucidated. While macrophages emerged as attractive effectors in tissue injury and repair, the contribution of specific macrophage subsets on cardiac cell function and survival in the steady state as well as in the diseased state is not fully understood. A better understanding of the role of myocardial inflammation post-MI is especially important for stem cell-based therapy, as most of the transplanted cells do not endure the inflammatory response and functionally couple with the resident cells in an ischemic environment. There are currently no appropriate in vitro experimental models to study the role of myocardial inflammation and macrophages, as existing models focus almost exclusively on mimicking the healthy cardiac microenvironment with the goal of providing a living surgical replacement. Thus, this proposal aims to investigate the role of macrophage subsets and the effect of myocardial inflammation on resident cardiomyocytes as well as on transplanted stem cells using both in vitro and in vivo models. A well-controlled in vitro diseased tissue model that can serve as a powerful tool to evaluate the heterocellular cross-talk during post-MI repair process will be developed. To complement and translate the findings from the in vitro diseased model, mouse MI models exhibiting either enhanced or suppressed inflammation will be utilized. Detailed and more mechanistic insights into macrophage interaction with the resident cells as well as transplanted stem cells as ?repair cell? during multi-phase repair process opens the possibility of exploring macrophage modulation as new therapeutic strategy. The results from this study will provide the basis for approaches to enhance acute retention and survival of the transplanted cells in the diseased tissue, which can ultimately lead to enhancing the efficacy of a cell-based therapy.